This grant proposes important laboratory studies of the mechanisms of action and toxicology of inhaled nitric oxide (NO). Our laboratory has reported that inhaling low levels of nitric oxide is a selective pulmonary vasodilator that reverses hypoxic pulmonary vasoconstriction. NO has mixtures were used to resuscitate hypoxic newborn sheep and treat diffuse acute lung injury. Inhaling nitric oxide improves the matching of pulmonary ventilation with perfusion in the Adult Respiratory Distress Syndrome (ARDS). Inhaled NO is also a rapid and profound bronchodilator in animal models. This grant proposes laboratory studies to examine the interaction of endogenous and exogenous pulmonary NO production, and to learn whether NO synthase inhibitors can augment the beneficial effects of NO inhalation in septic lung injury. In hypoxic newborn sheep the effects of respiratory and metabolic acidosis on NO induced pulmonary vasodilation will be explored. In guinea pigs the effects of NO will be examined on airway tone augmented by inflammatory stimuli (leukotrienes). A careful pathological analysis will be undertaken searching for any toxic effects of inhaling NO for periods up to one month upon normal adult and newborn rat lungs. In this manner our understanding will be enhanced of the safety of NO inhalation as a therapeutic agent in states of bronchospasm, pulmonary vasoconstriction, and diffuse acute pulmonary inflammation.